The Section on Developmental Genetics conducts both laboratory and clinical investigations to understand the molecular mechanisms of complex genetic disorders of neurodegenerative, inflammatory and autoimmune diseases in order to develop novel and rational therapeutic approaches. Towards these goals, the laboratory research of this Section is focused on understanding the regulation and physiological functions of primarily two genes: (1) uteroglobin (UG), also known as Clara cell 10 kDa protein (CC10), and (2) palmitoyl-protein thioesterase-1 (PPT1). Inactivating mutations in the PPT1 gene is the genetic basis of infantile neuronal ceroid lipofuscinosis (INCL), also known as infantile Batten disease. INCL is a devastating neurodegenerative storage disease of childhood. for which there is no effective treatment. UG-knockout mice develop immunoglobulin A (IgA)-nephropathy, a primary renal glomerular disease that often lead to kidney failure. This disease also does not have an effective treatment. Laboratory investigations in INCL have led to a bench-to-bedside clinical trial, which is currently ongoing. Recently, using PPT1-knockout (PPT1-KO) mice, which recapitulates virtually all clinical and pathological features INCL, we uncovered, for the first time that tPPT1-deficiency leads to endoplasmic reticulum (ER) stress (ER stress), which activates the unfolded protein response mediating apoptotic death of neurons, a characteristic finding in INCL. The results of our experiments not onlt provide insight into a complex mechanism of neurodegeneration in INCL but also identifies several potential targets for the development of rational and novel therapeutic approaches for this uniformly fatal disease. **Publications: Lee, Y.-C., Zhang, Z., Hitomi, E. and Mukherjee, A.B. (2006). Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. FEBS Lett. 580, 4515-4520, 2006. Kim SJ, Zhang Z, Hitomi E, Lee YC and Mukherjee A. B. Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL.Hum Mol Genet. 15, 1826-1834, 2006. Kim SJ, Zhang Z, Lee YC and Mukherjee AB.(2006) Palmitoyl-protein thioesterase-1deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Hum Mol Genet. 15,1580-1586, 2006.Zhang Z, Kim SJ, Chowdhury B, Wang J, Lee YC, Tsai PC, Choi M. and Mukherjee AB.Interaction of uteroglobin with lipocalin-1 receptor suppresses cancer cell motility and invasion. Gene. 369, 66-71, 2006.Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A. and Mukherjee AB. (2006). Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum MolGenet. 15, 337-346, 2006.Eisenstein EM, Choi M (2006) Analysis of a uteroglobin gene polymorphism in childhood Henoch-Schonlein purpura. Pediatr Nephrol 21:782-4; Zhang, Z., Kim, S.-J., Lee, Y.-C., Ray, R., Wang, J.-Y., Chowdhury, B., Choi, M.S.,Tsai, P.-C. and Mukherjee, A.B. (2005) Interaction of Uteroglobin with Lipocalin-1 Receptor. Gene. 369:66-71, 2006.Mandal, A.K., Zhang, Z. and Mukherjee, A.B. Yin-yang: balancing act of prostaglandins with opposing functions to regulate inflammation. .J. Immunol, Cutting Edge. 75, 6271-6273, 2005.Choi, M. S., Anderson, M.A., Zhang, Z., Zimonjic, D.B., Popescu, N. and Mukherjee, A.B. Neutral ceramidase gene: Role in regulating ceramide-induced apoptosis. (2003) Gene315:113-122;Chandra, S., Davis, J.M., Drexler, S., Kowalewska, J., Koo, H. C., Chester, D., Pollack, S., Welch, R, Pilon, A. and Levine, C.R. (2003) Pediatr Res. (2003)54:509-515; Chowdhury B, Mantile-Selvaggi G, Miele L, Cordella-Miele E, Zhang Z, Mukherjee AB. Lys 43 and Asp 46 in alpha-helix 3 of uteroglobin are essential for its phospholipase A2 inhibitory activity. Biochem Biophys Res Commun. 2002, 295:877-83; Wang CY, Lei HJ, Huang CY, Zhang Z, Mukherjee AB, Yuan CJ. Induction of cyclooxygenase-2 by staurosporine through the activation of nuclear factor for IL-6 (NF-IL6) and activator protein 2 (AP2) in an osteoblast-like cell line. Biochem Pharmacol. 2002 Jul 15;64(2):177-84; Mandal AK, Zhang Z, Chou JY, Mukherjee AB. Pancreatic phospholipase A2 via its receptor regulates expression of key enzymes of phospholipid and sphingolipid metabolism. FASEB J. 2001 Aug;15(10):1834-6. No abstract available. Mandal AK, Zhang Z, Chou JY, Zimonjic D, Keck CL, Popescu N, Mukherjee AB. Molecular characterization of murine pancreatic phospholipase A(2). DNA Cell Biol. 2001 Mar;20(3):149-57; Zhang Z, Butler JD, Levin SW, Wisniewski KE, Brooks SS, Mukherjee AB. Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med. 2001 Apr;7(4):478-84. Momeda K, Zhang Z, Mukherjee AB, Dhanireddy R. A novel in situ method of SV40 transfection for the establishment of immortal pulmonary alveolartype II cell lines. Ann N Y Acad Sci. 2000;923:325-31. Chowdhury B, Mantile-Selvaggi G, Kundu GC, Miele L, Cordella-Miele E, Zhang Z, Mukherjee AB. Amino acid residues in alpha-helix-3 of human uteroglobin are critical for its phospholipase A2 inhibitory activity. Ann N Y Acad Sci. 2000;923:307-11. Review. No abstract available. Choi M, Zhang Z, Ten Kate LP, Collee JM, Gerritsen J, Mukherjee AB. Human uteroglobin gene polymorphisms and genetic susceptibility to asthma. Ann N Y Acad Sci. 2000;923:303-6. Zhang Z, Kundu GC, Zheng F, Yuan CJ, Lee E, Westphal H, Ward J, DeMayo F, Mukherjee AB. Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches. Ann N Y Acad Sci. 2000;923:210-33; Zhang Z, Mandal AK, Mital A, Popescu N, Zimonjic D, Moser A, Moser H, Mukherjee AB. Human acid ceramidase gene: novel mutations in Farber disease. Mol Genet Metab. 2000 Aug;70(4):301-9. Yuan CJ, Mandal AK, Zhang Z, Mukherjee AB. Transcriptional regulation of cyclooxygenase-2 gene expression: novel effects of nonsteroidal anti-inflammatory drugs. Cancer Res. 2000 Feb 15;60(4):1084-91. Zheng F, Kundu G, Zhang Z, Mukherjee AB, Ward J, DeMayo F. Identical glomerulopathy in two different mouse models of uteroglobin deficiency. Am J Kidney Dis. 2000 Feb;35(2):362-3. Mantile G, Fuchs C, Cordella-Miele E, Peri A, Mukherjee AB, Miele L Stable, long-term bacterial production of soluble, dimeric, disulfide-bonded protein pharmaceuticals without antibiotic selection. Biotechnol Prog. 2000 Jan-Feb;16(1):17-25 Nemir M, Bhattacharyya D, Li X, Singh K, Mukherjee AB, Mukherjee BB. Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency. J Biol Chem. 2000 Jan 14;275(2):969-76.Zheng F, Kundu GC, Zhang Z, Ward J, DeMayo F, Mukherjee AB.Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Nat Med.5: 1999 1018-25;Loss of transformed phenotype in cancer cells by overexpression of the uteroglobin gene. Proc Natl Acad Sci1999 Mar 30;96(7):3963-8; Zhang Z, Mandal AK, Wang N, Keck CL, Zimonjic DB, Popescu NC, Mukherjee AB. (1999)Palmitoyl-protein thioesterase gene expression in the developing mouse brain and retina: implications for early loss of vision in infantile neuronal ceroid lipofuscinosis.Gene. 231(1-2):203-11.